Among millions of persons worldwide who survive an ischemic stroke or transient ischemic attack (TIA) each year, a major source of morbidity and mortality is recurrent stroke and myocardial infarction. Within 5 years of the initial event, 18-25% of patients will have a recurrent stroke, 9-10% will have a myocardial infarction, and 10-12% will die from one of these conditions. Prevention of further vascular events, therefore, is of major importance in reducing the morbidity and mortality of stroke and TIA. Current strategies to prevent recurrent vascular events include antiplatelet therapy, hypertension control, anticoagulation, lipid management, and carotid endarterectomy. Despite these effective strategies, each year 4-8% of suitably treated patients still experience recurrent vascular events. New therapies are urgently needed. The Insulin Resistance Intervention after Stroke (IRIS) trial is a randomized, double-blind, placebo-controlled study that is seeking to meet this need. IRIS is testing the effectiveness of pioglitazone for lowering the risk for stroke or myocardial infarction among men and women with a recent ischemic stroke or TIA and insulin resistance. Pioglitazone is a medication that lowers insulin resistance. Insulin resistance is a common, novel risk factor for stroke and other vascular diseases. It is also, along with failed pancreatic secretion of insulin, one of the 2 main causes of diabetes. Pioglitazone prevents diabetes, but its affect on vascular events, including stroke and myocardial infarction, are unproven. Eligible patients for IRIS are at least 40 years of age, non-diabetic, and insulin resistant according to an index based on fasting insulin and glucose values. Recruitment began in 2004, and 1,458 patients from over 90 sites in 3 countries have been randomized. Recruitment of 3,136 participants will be completed in 2010. All patients will be followed for a minimum of 3 years (average of 4). Assuming an outcome rate of 27% at 4 years for placebo recipients, IRIS has 90% power to detect a 20% reduction in risk for the primary endpoints of fatal and non-fatal stroke and myocardial infarction.